Pathways for the mutagenesis of 1-nitropyrene and dinitropyrenes in the human hepatoma cell line HepG2
- Case Western Reserve Univ., Cleveland, OH (United States); and others
The mutagenicity, metabolism, DNA adduction and induction of unscheduled DNA synthesis (UDS) of 1-nitropyrene and 1,8-dinitropyrene were investigate in the human hepatoma cell line HepG2. Previous results had demonstrated that 1-nitropyrene was both mutagenic at the hgprt locus and induced UDS in these cells. In the present study, we find that the dinitropyrenes, although highly mutagenic in Salmonella typhimurium, are not mutagenic and do not induce UDS in the HepG2. Although the rate of 1,8-dinitropyrene nitroreduction was less than that of 1-nitropyrene nitroreduction, this did not explain the lack of mutagenicity and UDS induction by the dinitropyrenes. Therefore, it is proposed that the arylhydroxylamine O-esterificase is not expressed in these cells. Since cytochrome P450-mediated C-oxidation is the predominant metabolic pathway in vivo, we sought to determine if an increase in the ratio of cytochrome P450-mediated C-oxidation over nitroreduction would result in increased or decreased DNA adducts in the HepG2. The administration of 2.5 {mu}M 3-methylcholanthrene to the HepG2 increased the ratio of C-oxidation/nitroreduction from 2.8 {+-} 1.9 to 50.4 {+-} 46.1. This was accompanied by a decrease in the C8-guanyl adduct of 1-nitropyrene (via nitroreduction) from 18.7 {+-} 7.0 to 4.8 {+-} 1.7 fmoles/{mu}g DNA, without any further increase in other 1-nitropyrene DNA adducts. These results suggest that the cytochrome P450-mediated metabolism of 1-nitropyrene to epoxides, phenols, and dihydrodiols is not an activation pathway in the HepG2 cells, and may explain the weak carcinogenicity of 1-nitropyrene in vivo, where cytochrome P450-mediated C-oxidation predominates. 54 refs., 4 figs., 3 tabs.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 478802
- Report Number(s):
- CONF-9210376--
- Journal Information:
- Environmental Health Perspectives, Journal Name: Environmental Health Perspectives Journal Issue: Suppl.6 Vol. 102; ISSN 0091-6765; ISSN EVHPAZ
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
3-METHYLCHOLANTHRENE
55 BIOLOGY AND MEDICINE
BASIC STUDIES
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
BENZOPYRENE
BIOLOGICAL EFFECTS
COMBUSTION PRODUCTS
CYTOCHROMES
DIESEL FUELS
DNA ADDUCTS
EXHAUST GASES
METABOLISM
MUTAGENESIS
NITRO COMPOUNDS
RISK ASSESSMENT
SALMONELLA TYPHIMURIUM
STRUCTURE-ACTIVITY RELATIONSHIPS